1. Field of the Invention
The present invention relates to novel compounds effective for prevention and treatment of various diseases associated with abnormal angiogenesis, and to the medical compositions such as angiogenesis inhibitors and antitumor agents containing the novel compounds.
2. Related Background of the Invention
Angiogenesis is an essential biological phenomenon for fetal vascular formation and morphological and functional development of organs. New blood vessels are assembled through several processes including endothelial cell migration, proliferation and tube formation, and the participation of mast cells, lymphocytes, interstitial cells and the like has been shown to be important in this process (non-patent literature 1).
A multiple in vivo angiogenesis-stimulating factors have been identified, particularly Vascular Endothelial Growth Factor (hereinafter abbreviated as “VEGF”) and Fibroblast Growth Factor (hereinafter abbreviated as “FGF”) are reported to enhance angiogenesis (non-patent literature 2 and 3).
Although physiological angiogenesis occurs at the time of healing of wound or in a female estrous cycle in adult individuals, it is known that pathological increase in angiogenesis in adult individuals is involved in onset or progression of various disease. Specific diseases associated with abnormal angiogenesis include cancer, rheumatoid arthritis, atherosclerosis, diabetic retinopathy, angioma, psoriasis, and the like (non-patent literature 4). In particular, a literature has indicated angiogenesis dependency for solid tumor growth, and angiogenesis inhibitors are therefore promising as new therapeutic agents for intractable solid tumors (non-patent literature 5).
Patent literature 1 and 2 are provided as prior arts with regard to 6-membered nitrogen-containing aromatic derivatives bonded with substituted indole.
Although patent literature 1 describes indole derivatives which suppress VEGF-stimulated angiogenesis based on a selective tyrosine kinase inhibition, the pharmacological test results on their inhibition action are not disclosed. Although patent literature 2 describes pyridine derivatives bonded with indole ring via an oxygen atom at the 4-position, neither the compound according to the present invention nor their inhibiting actions on FGF-stimulated angiogenesis are disclosed.    [patent literature 1] WO 02/16348    [patent literature 2] WO 02/32872    [non-patent literature 1] J. Biol. Chem., 267, 10931, 1992.    [non-patent literature 2] Endocrinology, 133, 848, 1993.    [non-patent literature 3] Biochem. Biophys. Res. Commun., 147, 876, 1987.    [non-patent literature 4] N. Engl. J. Med., 333, 1757, 1995.    [non-patent literature 5] J. Natl. Cancer Inst., 82, 4, 1990.